Notes
anthracene hydrochloride was active at 160 mg/kg (the only level tested) against P. gallinaceum in chickens. The increased antimalarial activity of these 1O-halo-9anthryl amino alcohols, along with the generally higher activity of the unsubstituted 9-anthryl amino alcohols over the unsubstituted 9-phenanthryl amino alcohols6 indicates that substituents in other positions on the anthracene nucleus should lead to enhanced antimalarial activity. Further credence for such a conclusion lies again in the 9-phenanthryl amino alcohols, where the symmetrical (Le., 3,6-) dihalo or bis(trifluoromethy1) substituents markedly increase the antimalarial activity.6’We plan the preparation of additional substituted anthracene amino alcohols. Experimental Section# Preparative methods and physical properties for the substituted 9-anthraldehydes prepared are given in Table I. The target compounds listed in Table I1 were prepared by the method of Duncan, et aL,’ using a 2-fold excess of ylid. lO-Chloro-9-antluonitrile. 10-Chloro-9-anthraldehydewas refluxed with NH,OH.HCl and HC0,Na in HC0,H2’ for 3 hr. The resulting soin was cooled and filtered to give, in 96% yield, crude lO-chloro-9-anthronitrile, mp 238-241’. Six recrystns from HOAc gave mp 256-257’, lit.30 255”. Anal. (C,,H,ClN) C, H, N. lO-Chloro-9-vinylantluacene. To a yellow suspension of 5.5 mmoles of triphenylphosphonium methylide (prepared3’ under N from tert-BuOK-tert-BuOH in THF and methyl triphenylphosphonium iodide in Et,O) was added 1.20 g ( 5 mmoles) of 10chloro-9-anthraldehyde in 50 ml of THF (refluxed over and distd from NaH) dropwise over ca. 10 min. The resulting yellow mixture was stirred at 25” for 1 hr and concd on a rotary evaporator at 65’ to give a yellow-green semisolid, which was extd 3 times with 50, 25, and 25 ml of hot petr ether. After cooling the combined extracts, the resulting yellow-orange crystals were filtered and discarded, as was the next crop, obtained after concg to 1 5 ml. The following two crops (0.76 g, 68% yield) of crude 10-chloro-9-vinylanthracene had mp 107-1 13’. Recrystn from EtOH and petr ether gave mp 113-114’. Anal. (C,,H,,Cl) C, H.
Acknowledgment. We express our appreciation to Drs.
J o u m l o f Medicinal Chemistry, 1972, Vol. 15, No. 8
863
R. E. Strube, Amino Alcohol Antimalarial Conference, Walter Reed Army Institute of Research, Washington, D. C., May 1969. L. F. Fieser, J. L. Hartwell, and J. E. Jones, “Organic Syntheses,” Collect. Vol. 111, Wiley, New York, N. Y., 1955, p 98. V. I. Rogovick, V. A. Lavrischchev, and V. I. Tikhanov, J. Org. Chem. USSR, 3,1275 (1967). E. D. Bergmann and E. Loewenthal, Bull. SOC.Chim. Fr., 66 (1952). R. Kuhn and H. Fischer, Chem. Ber., 94, 3060 (1961). G. Kalischer, H. Scheyer, and K. Keller, U. S. Patent 1,717,567 (June 18.1929): Chem. Abstr.. 23.3933 (1929). (12) J. Tiroflet, Buli.’Soc. Sci. Bretagne; 26, 7 (1951); Chem. Abstr., 47, 8692 (1953). (13) J. Tiroflet,Bull. SOC.Sci. Bretagne, 26,45 (1951). (14) Netherlands Application 6,414,607 (June 21, 1965); Chem. Abstr., 64,703 (1966). (15) E. D. Barnett and M. A. Mathews, J. Chem. SOC.,123,380 (1923). (16) J. G. Topliss, L. M. Konzelman, N. Sperber, and F. E. Roth, J. Med. Chem., 7,453 (1964). (17) F. C. Appleby, Chem. Znd. (London), 120 (1971). (18) E. J . Corey and M. Chaykovsky, J. Amer. Chem. SOC.,87, 1353 (1965). (19) R. R. Burtner and J. W. Cusic, J. Amer. Chem. Soc., 65,265 (194 3). (20) D. Ginsberg, ibid., 73,702 (1951). (21) M. Arai, Nippon Kagaku Zashi, 81,1450 (1960); Chem. Abstr., 56,2370 (1962). (22) G. Berger and S. C. J. Oliver, Red. Trav. Chim. Pay-Bas, 46, 600 (1927). (23) G. B. Payne, Tetrahedron, 18,763 (1962). (24) G. E. Chivers and H. Suschitzkey, J. Chem. SOC.D , 28 (1971). (25) W. E. Hanby and W. N. Rydon, J. Chem. SOC., 114 (1946). (26) L. Krbechek, R. Riter, R. Wagner, and C. W. Huffman, J. Med. Chem., 13,234 (1970). (27) J. T. Traxler, L. Krbechek, R. Riter, R. Wagner, and C. W. Huffman, ibid., 14,90 (1971). (28) T. S . Osdene, P. B. Russell, and L. Rane, ibid., 10,431 (1967). (29) T. VanEs, J. Chem. Soc., 1564 (1965). (30) G. Lohaus, Chem. Ber., 100,2719 (1962). (31) M. Schlosser and K. F. a i s t m a n n , Angew. Chem., 76,683 (1964).
T. E. Sweeney and R. Strube of Walter Reed Army Institute of Research and Professor R. P. Mariella of Loyola University for helpful advice and to Mrs. Diane Dalton for technical assistance. References (1) F. Y. Wiselogle, “A Survey of Antimalarial Drugs: 19411945,” J. W. Edwards, Ann Arbor, Mich., 1946. (2) E. L. May and E. Mosettig, J. Org. Chem., 11,353 (1946). (3) G. R. Coatney, W. C. Cooper, N. B. Eddy, and J. Greenberg, “Survey of Antimalarial Agents,” Public Health Monograph No. 9, Washington, D. C., 1953, p 182. (4) E. L. May and E. Mosettig, J. Amer. Chem. SOC.,70,686 (1948). (5) W. G. Duncan, W. T. Colwell, C. R. Scott, and D. W. Henry, J. Med. Chem., 11,1221 (1968).
#The chemicals employed in this investigation were used as obtained from chemical supply houses without purification unless otherwise noted. Melting points were determined with a ThomasHoover capillary melting point apparatus and have not been corrected. Most reactions and purification procedures were followed by tlc on Gelman SG sheets; a convenient general purpose solvent system for these compounds on this medium is 5-15% Et,O in petroleum ether (60-1 10’). Target hydrochlorides were separated on Mallinckrodt Chromar 1000 in a similar solvent system after over spotting with dilute Et,N in THF. Visualization was accomplished with shortwave uv, 0.2% KMnO, in 1.0%aqueous Na,CO,, 0.4% Bromophenol Blue in MeOH (for bases; adjust to pH = 8 for acids), or 0.04% 2,4-dinitrophenylhydrazinein 2 N HCI. Ir spectra were detd on a Beckman IR 5A prism instrument and nmr spectra were detd at 60 MHz by W. Simon Associates, Elgin, Ill. Elemental analyses were carried out with a Hewlitt Packard Model 185 CHN analyzer by the IMC Organic Analysis Group under the supervision of Mr. L. Ferrara. When analyses are indicated only by the symbols of the elements, the results were within f0.4% of the theoretical values.
3-Chromanamine Hydrochlorides with Central Stimulant Activity Ian M. Lockhart* and Sheila A. Foard Chemical Research Department, Research and Development Division, Parke, Davis and Company, Hounslow, Middlesex, England. Received March I 7, 19 72
The synthesis of a number of 3-chromanamine hydrochlorides that reduce the hyperirritability of rats that have been lesioned in the septal area of the brain and/or which suppress the killer instinct in rats has been carried out in these laboratories.’ Many of these compounds caused some central excitation in rats as determined by the increase in locomotor activity determined with jiggle cages? using the procedure of Schulte, et al. However, when some 3-chrom anamine hydrochlorides with two alkyl groups in the aromatic ring were studied, it was found that many of them were potent stimulants when examined by this technique. This paper describes the preparation of such compounds and the examination of their stimulant activity. Chemistry. The 3-chromanamine hydrochlorides have been prepared from 3-amino-4-chromanonehydrochlorides by conventional synthetic methods. Their physicochemical +Author t o whom correspoadence should be addressed at R o chem, The British Oxygen Company Limited, London, SW19 3UF, England. TD. A. McCarthy, unpublished observations.
864 Journal OfMedicinal Chemistry, 1972, Vol. 15, No. 8
Notes
Table I. 3-Chromanamine Hydrochlorides
Compd 1 2 3 4 5
6 7 8 9
10 11 12 13 14 15
16
R' 5,7-Me2 5,7-Mez 5,7-Me, 5,7-Me, 5,7-Me, 5,7-Me, 5-Me, 8-i-Pr 5-Me, 8-i-Pr 6,7-Me2 6,7-Me2 6,8-Mez
RZ H H H Me H Me H Me H H H
R3 H Me Et Me H Me H Me H Me H
R4 H H H H Me Me H H H H H
Method A B C D A D
6,8-Me, 7,8-Me, 7,8-Me2 7,8-Me, 6-C1,5-Me, 8-i-Pr
H H H Me H
Me H H Me H
H H Me Me H
B
A
D A B
A A A
D E
Mp,"C 207.5 194-195 256-257 243-245 243-245 229-230 267-269 187-189 270-279f 234-235 285-287 219-220 244-246 240-241 207-209 223-224
Form
Crystd form
Yield, %
C
g
d d d d d d d
h h h h h h h h h h
76 35 46 54 24 36 59 69 65 52 69
h h h h g
63 60 35 61 56
c
c d d
e d d d
Formulaa C,,H,,ClNO C,,H, &IN0 C,,HzoCINO C,,HzoCINO C,,H,,ClNO C,4H,,ClN0 C,,H,,ClNO C,,H,,CINO C, ,H,,ClNO C,,H,,ClNO C,,H,,ClNO~ OSH,O C,,H,,ClNO C, H, ,CINO~ C,,H,,CINO C,,H,,CINO
,
1'
BH I9"ZN0
'
Increase in motor activityb 6 3 100 N 6 13 3 25 N
100 N 3 N
0.5H,OJ 'All compounds were analyzed for C, H, N. bLowest dose at which increase is comparable with effect of caffeine administered at !3 mg/kg sc. N indicates inactive at 100 mg/kg sc. 'Rods. %sms. 'Needles. fWith sublimation and decomposition. gEtOH-Et,O. hEtOH. 'C: calcd, 61.8; found, 62.5. IC: calcd, 54.7; found, 54.2.
properties are collected in Table I and the following experimental details relate to that table. Pharmacology. The central excitatory activity of the 3chromanamine hydrochlorides was measured by the increase of motor activity in rats in jiggle cages of the type described by Schulte, et al.' The drugs were administered subcutaneously to groups of six male albino rats at each graded dose level. The results are collected in the last column of Table I. The figure given indicates the lowest dose at which the compound caused an increase in motor activity comparable with that caused by caffeine administered at a dose of 13 mg/kg sc under the same conditions. Experimental Section 4-Chromanones were prepared and converted to 3-amino-4chromanone hydrochlorides by previously reported methods3 Subsequent reduction with NaBH, or LiAlH, afforded 3-amino-4chromanols. 3-Chromanamine Hydrochlorides Method A. The catalytic hydrogenation of 3-amino-4-chromanols in glacial HOAc-concd H,S04 at atmospheric pressure in the presence of 10% Pd/C afforded the appropriate 3-chromanamine hydrochlorides. N-Monomethyl-3-chromanaminesMethod B. Free amines were converted to their N-formyl derivatives by refluxing with 98% formic acid and AczO for 5 hr. The crude formamido compound was reduced with LiAlH, in Et,O to the N-monomethyl-3-chromanamine. N-Ethyl-5,7dimethyl-3-chromanamine Hydrochloride. Method C. 3-Amino-5,7-dimethyl-4-chromanone hydrochloride was converted to the N-acetyl derivative by the method reported previously.' The acetamidochromanone was hydrogenated in EtOH in the presence of 10% Pd/C, and the resulting acetamidochromanol was converted using GAM, in Et,O. to 3-amino-N-ethyl-5,7-dimethyl-4-chromanol A final hydrogenation in HOAc-H,SO, in the presence of 10% Pd/C afforded the N-ethylchromanamine. N,N-Dimethyl-3-chromanamine Hydrochlorides Method D. N,N-Dimethyl-3-chromanamines were prepared by refluxing the $Melting points are corrected and were determined in a capillary tube. Boiling points are uncorrected. Where analyses are indicated only by symbols of the elements, analytical results for those elements were within t0.40/0 of the theoretical values.
corresponding 3-chromanamines with 90% formic acid and 36% (w/v) HCHO for 7 hr. 6-Chloro-8-Lwpropyl-5-1nethyl-3-chromanamine Hydrochloride. Method E. 8-Isopropyl-5-methyl-3-chromanamine hydrochloride in CHCI, was chlorinated directly with C1, in CHCI, at room temperature.
Discussion An examination of the results reported in this paper showed that certain of the 3-chromanamine hydrochlorides produced a very strong stimulant effect in rats. Although only a limited number of compounds are reported here, many of those to be reported elsewherelb have been tested in jiggle cages but none were as active as the more potent members of this series.? It seemed, therefore, that the substitution of two alkyl groups in the aromatic ring of a 3chromanamine often had a profound effect on the stimulant proper ties. However, it was difficult to elucidate possible structural requirements for potent stimulant activity. For example, with the 2,7,8-trimethyl-3-chromanamine7 dimethylation of the amino group converted an inactive primary amine (14) to a very active tertiary amine (15). However, the reverse where a was true with the 5,7-dimethyl-3-chromanamine potent primary amine (1) on N-dimethylation was converted to an inactive tertiary amine (4). With the 2,5,7-trimethyl3-chromanamines, both the primary amine ( 5 ) and the tertiary amine (6) showed strong stimulant properties. The results reported here and elsewhere' illustrate some of the great variety of interests that 3-chromanamine hydrochlorides have to the medicinal chemist, The series also illustrates the very profound changes in biological activity that can occur as a result of relatively small changes in chemical structure. Acknowledgments. The authors are grateful t o Dr. R. E. Bowman for his constant advice and encouragement, and to Mr. F. H. Oliver for the microanalyses. We are particularly indebted to Dr. D. A. McCarthy and Mr. C. R. Ensor for the pharmacological studies and their evaluation.
Journal of Medicinal Chemistry, 1972, Vol. 15, No. 8
Notes
Table I. Substituted Chromones Synthesized
References (1) (a) I. M. Lockhart, British Patent, 1,151,474; (b) I. M. Lockhart, D. Huckle, M. Wright, and D. A. McCarthy, submitted for publication. (2) J. W. Schulte, E. C. Reif, J. A. Bocher, W. A. Lawrence, and M. L. Tainter,J. Pharm. Exp. Z'her., 71,62 (1941). (3) D. Huckle, I. M. Lockhart, and M. Wright, J. Med. Chem., 12, 277 (1969).
Benzopyrones. 7. Synthesis and Antiallergic Activity of Some 24 5-Tetrazolyl)chromones'
Antiallergic properties in the chromone series a ~ p e a r ~ - ~ to be largely confined to those compounds which contain a carboxyl group at C-2. Replacement of a carboxyl by a 5tetrazolyl group in a biologically active carboxylic acid5-' has sometimes resulted in retention of activity but rarely in an improvement in potency. This paper reports the synthesis and antiallergic properties of a number of chromones: such as Id and its substituted derivatives, which carry a 5-tetrazolyl group at C-2. The variations in structure are shown in Table I. Chemistry. The title compounds which are listed in Table I1 were prepared by the route shown in Scheme I.
0
-
CONH,
0 lb
la
I
Id
IC
The carboxylic esters, prepared14 from the appropriate 2hydroxyacetophenone and diethyl oxalate, reacted with gaseous NH3 at 0" to give high yields of the carboxamides. Although several carboxamides of this kind are known, their dehydration to the 4-oxo-4H-1-benzopyran-2-carbonitriles has not been reported. The unsubstituted carbonitrile IC, the only known member of this series, was synthesized12 in five stages from 2-methylchromone via the 2-carboxaldehyde. A more convenient method is now described through the dehydration of the carboxamide by means of an arylsulfonyl chloride and pyridine in DMF. Other reagents," such as POC13, PCl~.Pocl3,SOCl2, or P205, proved to be ineffective while benzenesulfonyl chloride in pyridine" gave a low yield. 3-Chloro-4-oxo-4H~ 1-benzopyran-2-carbonitrile(17c) was prepared by reacting the unsubstituted nitrile (IC)with sulfuryl chloride. The carbonitriles were converted smoothly to the tetrazoles by reaction with sodium azide and ammonium chloride in DMF.'l A recent study" showed that the pKa of ?Science Research Council Postgraduate Student.
X
b, R1 = CONH, c, R' = CN d, R1 = 5-tetrazolyl Compd No. 2
Department of Chemistry, University of Wales Institute of Science and Technology, Cardiff CFl 3NU, United Kingdom. Received January 12,I9 72
W C O Z E t
R3
a, R' = C0,Et
1
G. P. Ellis* and D. Shawt
Scheme I
865
3 4 5
6 7 8 9 10 11 12 13 14 15 16 17
Rz H Me H H H H H H H H H H H H H H C1
R3 H H H H H Me H H H H OMe H H H H H H
R4 H H Me H H H c1 Br Br Me H H H NO, NO2 H H
R5 H H H Me H Me H H H H H OMe OCH,Ph H H H H
R6 H H H H Me H H H Br Br H H H H Me H H
X 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 S
0
4-oxo-4H-l-benzopyran-2-carboxylicacid was 2.96. The low solubility of the corresponding tetrazole (Id) in water and ethanol caused difficulties in the accurate determination of its pKa but, using a potentiometric method, a value (2.8) was obtained which showed that the acidity of both carboxylic acid and tetrazole are comparable. Biological Results. The tetrazoles were screened for antiallergic activity in rats by means of the passive cutaneous anaphylaxis test using an extract of Nippostrongylus brasiliensis as antigen23and disodium cromoglycate as standard. Those compounds which showed activity comparable with or better than disodium cromoglycate are listed in Table 111. Although the nature of the test makes it difficult to quantify the results, Id, 3d, 4d,and 14d are appreciably more potent than the standard drug. Substitution by alkyl or halogen at C-3 or C-8 lowers activity as does the replacement of the 4 oxo by 4-thiOX0 group. The activity level is very susceptible to comparatively small changes in the substituents at C-7 (cx 4d,12d, and 13d). This study shows that a carboxyl group in chromone-2-carboxylic acids may be advantageously replaced by a tetrazolyl group which confers a comparable degree of acidity on the molecule. Four compounds, 2b, 2c, 9d, and 14b,showed activity similar to aspirin in reducing writhing induced by phenylquinonez4 but were almost inactive in the hot plate test." The oral LDso values of all the compounds in mice were greater than 100 mglkg. Experimental Section Melting points were determined on a Reichert hot stage apparatus using a calibrated thermometer. A low value for the N content of a few tetrazoles was obtained although the combustion time was incmsed as recommended by the manufacturers of the instrument (Hewlett Packard). General Method of Synthesis (a) Ethyl 4-Oxo-4H-l-benzopyran2-carboxylates. The esters were prepared by the method of Zagorevskii, et al. I' The following new substituted 4-oxo4H-l-benzopyran2-carboxylic acids (from EtOH) were obtained from the esters by hydrolysis with a mixture of HCl and AcOH (analyzed for C and H): 8-methyl-, mp 272-273" dec; 5,7dimethyl-, mp 251-252' dec;
